rs149868979

Variant names:

• chr16-23380566-G-A
• rs149868979
• NM_000336.3:c.1688G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-23380566-G-A
• chr16-23380566-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_000336.3(SCNN1B):​c.1688G>A​(p.Arg563Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,614,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R563W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.13
• Publications: 24 publications found

Genes affected

SCNN1B (HGNC:10600): (sodium channel epithelial 1 subunit beta) Nonvoltage-gated, amiloride-sensitive, sodium channels control fluid and electrolyte transport across epithelia in many organs. These channels are heteromeric complexes consisting of 3 subunits: alpha, beta, and gamma. This gene encodes the beta subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), and Liddle syndrome. [provided by RefSeq, Apr 2009]

SCNN1B Gene-Disease associations (from GenCC):

• Liddle syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism, type IB2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• bronchiectasis with or without elevated sweat chloride 1

  Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Liddle syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 16-23380566-G-A is Pathogenic according to our data. Variant chr16-23380566-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 561264.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP4: Computational evidence support a benign effect (MetaRNN=0.1114372). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1B	NM_000336.3	c.1688G>A	p.Arg563Gln	missense_variant	Exon 13 of 13	ENST00000343070.7	NP_000327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1B	ENST00000343070.7	c.1688G>A	p.Arg563Gln	missense_variant	Exon 13 of 13	1	NM_000336.3	ENSP00000345751.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251322 AF XY: 0.000162

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461840 Hom.: 1 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727230

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1112000

Other (OTH) AF: 0.000248 AC: 15 AN: 60396

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74514

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.00105 AC: 16 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Low renin, low aldosterone hypertension Pathogenic:1

Mar 10, 2018

GeneID Lab - Advanced Molecular Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in an amino acid alteration, replacing an arginine(R) with a glutamine (Q) at position 563, written as p.Arg563Gln or p.Q889H. . in silico prediction algorithms does not provide uniform data regarding the effect of this change on protein structure and function, and it has not been reported in the Clin Var Database (NCBI National Library of Medicine, NIH) but it has been described in 16 alleles out of 121124, in the ExAC database, the majority (9) belonging to heterozygous carries of Latino origin. The variant has been associated with low-renin, low-aldosterone hypertension in South African black and mixed-ancestry individuals, the authors conclude that only a portion of subjects with the R563Q allele fully express the Liddle’s syndrome phenotype (J Hypertens. 2003 May;21(5):921-6). Moreover, there is a positive correlation with pre-eclampsia in this population (BJOG. 2006 May;113(5):595-8). -

Bronchiectasis with or without elevated sweat chloride 1;C5774255:Pseudohypoaldosteronism, type IB2, autosomal recessive;CN031472:Liddle syndrome 1 Uncertain:1

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 563 of the SCNN1B protein (p.Arg563Gln). This variant is present in population databases (rs149868979, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of SCNN1B-related conditions (PMID: 12714866, 22895453, 28052878). ClinVar contains an entry for this variant (Variation ID: 561264). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCNN1B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1

Mar 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L;.;.;.
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.64	N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.090	B;.;.;.
Vest4		0.30
MVP		0.82
MPC		0.19
ClinPred		0.032	T
GERP RS		1.4
Varity_R		0.050
gMVP		0.54
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149868979; hg19: chr16-23391887;